O-benzoylthiamine bisulfide



United States Patent 3,109,000 O-BENZOYLTIHAMINE DISULFHDE Chikataro Kawasaki and Isamu Utsuini, Sakyo-ku, Kyoto,

Tadashi Fujita, Otsu, and Hiroshi Kobayashi, Nishinomiya, Japan, assignors to Tanabe Seiyaku (30., Ltd., Osaka, Japan No Drawing. Filed Aug. 30, 1961, Ser. No. 135,417 Claims priority, application Japan Oct. 5, 1960 1 Claim. (Cl. 260-2565) This invention relates to O-benzoylthiamiue disulfide which possesses vitamin B -like activity, and to its preparation.

It has been known that acid addition salts of thiamine have many deficiencies such as unpleasant odor, low stability, solubility in water or limited absorption upon oral ingestion, etc.

It has also been known that some people have thiaminase, thiamine destroying enzyme in their intestines. Therefore, no effects can be seen on such people by orally administering thiamine acid-addition salts.

According to this invention, we have found that 0 benzoylthiamine disulfide is free of the disadvantages of the above mentioned thiamine acid-addition salt, especially the hydrochloride. The O-benzoylthiamine disulfide of this invention occurs as colorless and odorless crystal melting at 146 to 147 C.

Its structural formula is as follows.

CH3 CH2CH2000C6HS 2 n has been found that O-benzoy-lthiamine disulfide is sparingly soluble in water. The solubilities in distilled water at various temperature are as follows.

TABLE I Solubilities (Percent) by weight/volume Temperature 0.)

3,109,000 Patented Oct. 729, 1963 TABLE II Residual Rate (Percent) in Aqueous Solution (2 mg./cc.) at C.

After 30 minutes After 60 minutes After minutes pH B'IDS BrHCl BTDS B11101 BTDS BiHOl (percent) (percent) (percent) (percent) (percent) (percent) pH 5.04.0: MaeElvains buffered solution. pH 8.0-9.0: Clark-Lubus bufiered solution.

TABLE III Residual Rate (Percent) in Calcium Carbonate Powder (200 mg./g.) [Relative humidity 82% at room temperaturel Substance After 5 After 25 After 40 days days days BlHCl 59 12 6 BTDS 100 94 94 It has been found that O-benzoylthiamine disulfide resists enzymatic degradation with thiaminase more strongly than thiamine hydrochloride on the test as described below.

The mixture of 1 m1. of substrate solution containing 20 of B H01 or 22.8 of BTDS (equivalent to 205 of B HCl), 1 ml. of buffered solution and 3 ml. of the enzymatic solution prepared from cultural medium of Bacillus thiaminolyticus (M.M.) or Bacillus aneurinolyticus (K.A.) was incubated for 1 hour at 37 C., and degradation rate of the substances Was assayed by thiochrorne method.

It has been also found that the compound of this invention possesses vitamin B -like, activity on tests on both animals and human being. Moreover, when orally administering the compound of this invention, it can be seen that blood level of total vitamin B reaches the peak more rapidly, providing longer durability as compared with thiamine hydrochloride, and a larger quantity of free vitamin B is excreted in urine as compared with thiamine hydrochloride. These mean better absorbability of the compound from the intestines than that of thiamine hydrochloride.

From the above facts, the O-benzoylthiamine of our invention is useful more advantageously than thiamine hydrochloride for the treatment of vitamin B -deficiency symptoms. It is also useful as fortifying agent suitable for use in those instances where a fortifying agent of low water-solubility is desired, for instance, in the enrichment of cereals subjected to rinsing before being cooked.

The present invention also comprises processes for preparing the O-benzoylthiamine disulfide. The O-benzoylthiamine disulfide may be prepared by reacting thiamine disultide with an acylating agent derived from benzoic acid such as chloride, bromide or anhydride in the presence of an acid acceptor such as sodium hydroxide,

sodium carbonate, potassium hydroxide, potassium carbonate or pyridine.

As the starting material, the oxidation mixture of thiamine in alkaline solution in which the thiamine disuliide is formed may also be used. Alternatively, the O-benzoylthiamine disuliide may also be prepared by treating O- benzoyltbiamine with an oxidizing agent such as iodine, hydrogen peroxide or potassium ferricyanide, while maintaining the pH of the reaction mixture at alkalinity.

It has been found that the reaction proceedsmost satisfactorily at a pH within the range of 10.0 to 12.0 in an aqueous medium.

The invention is further illustrated by the following examples without being limited thereto.

EXAMPLE 1 ml. of benzoyl chloride was dropped into a stirred suspension of g. of thiamine disulfide in 20 ml. of absolute pyridine at room temperature. The mixture was stirred an additional 3 hours at room temperature and was allowed to stand overnight. "The reaction mixture was concentrated under reduced pressure to remove pyridine and after adding small amounts of 20% aqueous solution of sodium hydroxide, the residue was extracted with chloroform. The extract was washed with small amounts of aqueous solution of sodium bicarbonate and water successively and 'was dried with sodium sulfate. Then the chloroform was removed by evaporation and 20 ml. of benzene was added to the residue whereby O- benzoylthiamine disulfide crystallized out.

Yield, "20 g., :colorless prisms melting at 146147 C., after recrystallizing from 99% ethanol.

Analysis-Calculated for C H OgN S C, 59.21; H, 5.49; N, 14.54. Found: C, 59.39; H, 5.79; N, 14.31.

Di-hydrochloride: Colorless prisms melting at 180"- 181" C. (decomp) Analysis.Calculated for C H OQN S -ZHCI-ZH O: C, 51.88; H, 5.50; N, 12.74. Found: C, 52.02; H, 5.57; N, 12.74. i

EXALLPLE 2 20 g. of thiamine disulfide was suspended in 200 ml. of water and 3.5 g. of concentrated hydrochloric acid was added to the suspension to dissolve the particles. The mixture was made alkaline-With sodium hydroxide. 10 ml. of benzoyl chloride was dropped into the mixture with stirring on an ice bath. 'During the period, pH of the mixture was kept in alkalinity with 20% aqueous solution of sodium hydroxide. The mixture was stirred for anadditional 3 hours at room temperature. After being adjusted to pH 7, the mixture was extracted with chloroform and the extract was treated as described in Example 1. 18 g. of O-benzoylthiamine disulfide was obtained.

EXAMPLE 3 The procedure described in Example 1 was followed except that 20 g. of benzoic anhydride was used instead of benzoyl chloride. 16 g. of O-benzoylthiamine disulfide was obtained.

EXAMPLE 4 24 g. of sodium hydroxide in 140 ml. of water was the mixture at room temperature with stirring. During the period, pH was held in alkalinity with sodium hydroxide. After being allowed to stand overnight,; the reaction mixture Was extracted with chloroform and the extract was treated as described in Example 1. 50 g. of O-benzoylthiamine disulfide was obtained.

EXAMPLE 5 4.5 g. of O-benzoylthiamine in 460 ml. of water was neutralized-with 7 .5 ml. of 4 N sodium hydroxide on an ice bath. Into the solution, was dropped a solution comprising 1.3 g. of iodine, 4 g. ofsodiurn iodide and ml. of water at the same temperature with stirring. As the reaction proceeds, white precipitates appeared. The mixture was stirred for an additional 10 minutes, and the precipitates were extracted with ethyl acetate.

After the extract was washed with water and dried, ethyl acetate was evaporated at a reduced pressure and 30 m1. of benzene was added to the residue whereby O- benzoylthiamine disulfide crystallized out.

Yield 2.9 g., 75.3% of theory.

EXAMPLE 6 i CHa-C N-CH 3 CHzCHzOCOCaHs 2 References Cited in the file of this patent UNITED STATES PATENTS 2,458,453 Warnat Jan. 4, 1949 2,752,348 Matsukawa et a1 June 26, 1956 2,833,768 Fujiwara et a1. May 6, 1958 3,064,400 Ito et a1 Nov. 13, 1962 OTHER REFERENCES Rosenberg: Chemistry and Physiology of the Vitamins (New York, .1945), pages 120, 143-4, 134-5; 100-104. QP 801. V5 R8.

Hickinbottom: Reactions of Organic Compounds (London, 1948), pages 96-99.

Williams et al.: The Biochemistry of B Vitamins (New York, 1950), pages 361-370, QP 801 V5 B6.

Zima et'al.: Die Naturwissenschaften, 41, 214 (1954). 

